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Effect of cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca 2+ ‐ATPase, on the frequency‐dependence of the contraction‐relaxation cycle of the guinea‐pig isolated atrium
Author(s) -
Yard Nicola J.,
Chiesi Michele,
Ball Howard A.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17092.x
Subject(s) - cyclopiazonic acid , contraction (grammar) , endoplasmic reticulum , chemistry , stimulation , biophysics , guinea pig , medicine , atpase , muscle contraction , endocrinology , biology , biochemistry , enzyme
1 The relevance of a functional sarcoplasmic reticulum (SR) membrane system to the contraction‐relaxation cycle and to the force‐frequency relationship of guinea‐pig atrial tissue was investigated. Cyclopiazonic acid (CPA) was used to inhibit selectively the activity of the SR Ca 2+ ‐ATPase. IQo values of 0.2 μ m or 1.0 μ m were measured in guinea‐pig isolated SR membranes in the absence or presence of millimolar ATP, respectively. CPA (0.3–30 μ m ) did not inhibit the activity of the sarcolemmal Na + ‐Ca 2+ ‐exchanger as measured in isolated cardiac cell membrane preparations. 2 In guinea‐pig isolated left atrium paced at 2.5 Hz (30°C), CPA (1–100 μ m ) produced a concentration‐dependent reduction in developed tension and a fall in the maximum rate of tension increase (+ d T/ d t max ) and decrease ( ‐d T/ d t max ). The twitch duration was markedly increased due to a prolongation of the time to peak tension, and in particular, the relaxation phase. 3 The contraction‐relaxation cycle of the left atrium showed a marked dependence on the frequency of stimulation. The developed tension and + d T/ d t max showed a progressive increase from 0.5 Hz, reaching peak values at a stimulation rate of 1.5‐2.5 Hz, the positive staircase phenomenon. Higher frequencies of stimulation caused a fall in these parameters. Resting tension was unaffected. The time‐course of the contraction‐relaxation cycle was also frequency‐dependent, with both time to peak tension and relaxation time showing a progressive fall from 2.0–3.5 Hz. 4 The addition of CPA (30 μ m ) caused marked alterations in the frequency‐dependence of the contraction‐relaxation cycle. The frequency‐dependence of developed tension, + d T/ d t max , was shifted downwards, particularly at higher frequencies, and the frequency at which peak values of + d T/ d t max and — d T/ d t max were reached was shifted leftwards. The resting tension of the tissues in the presence of 30 μ m CPA was increased markedly at frequencies greater than 2 Hz. The time‐course of the contraction‐relaxation cycle was markedly prolonged between 1.0 and 3.5 Hz, due to an effect on both time to peak tension and relaxation time. 5 In conclusion, these results show that CPA is a highly selective inhibitor of the cardiac SR Ca 2+ ‐ATPase, without effect on the sarcolemmal Na + ‐Ca 2+ ‐exchanger, and suggest that a functional SR Ca 2+ ‐ATPase is necessary for the normal contraction‐relaxation cycle of guinea‐pig cardiac tissue. Additionally, the results suggest an increasing dependence of tension development on SR Ca 2 +‐ATPase with increasing frequency, which may reflect either a frequency‐dependent activation of this enzyme or the diminished contribution of the Na + ‐Ca 2+ exchanger. These results also provide novel support for the mechanism of the depressed force‐frequency relation found in cardiac tissue of heart failure patients, in which there is a reduced expression of Ca 2+ ‐ATPase.